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Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core

  1. Author:
    Tian, Jianhua
    Teuscher, Kevin B.
    Aho, Erin R.
    Alvarado, Joseph R.
    Mills, Jonathan J.
    Meyers, Kenneth M.
    Gogliotti, Rocco D.
    Han, Changho
    Macdonald, Jonathan D.
    Sai, Jiqing
    Shaw, J. Grace
    Sensintaffar, John L.
    Zhao, Bin
    Rietz, Tyson A.
    Thomas, Lance R.
    Payne, William G.
    Moore,Bill
    Stott,Gordon
    Kondo, Jumpei
    Inoue, Masahiro
    Coffey, Robert J.
    Tansey, William P.
    Stauffer, Shaun R.
    Lee, Taekyu
    Fesik, Stephen W.

  2. Author Address

    Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA.Vanderbilt Univ, Sch Med, Dept Cell & Dev Biol, Nashville, TN 37232 USA.Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA.Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA.Vanderbilt Univ, Vanderbilt Inst Chem Biol, Dept Chem, Nashville, TN 37232 USA.Vanderbilt Univ, Vanderbilt Inst Chem Biol, Chem Synth Core, Nashville, TN 37232 USA.Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD 21701 USA.Kyoto Univ, Grad Sch Med, Dept Clin Bioresource Res & Dev, Kyoto 6068501, Japan.Osaka Int Canc Inst, Dept Biochem, Osaka 5418567, Japan.
    1. Year: 2020
    2. Date: JAN 23
  2. Journal: JOURNAL OF MEDICINAL CHEMISTRY
  3. AMER CHEMICAL SOC,
    1. 63
    2. 2
    3. Pages: 656-675
  5. Type of Article: Article
  6. ISSN: 0022-2623
  1. Abstract:

    WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.

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External Sources

  1. View Full Text
  2. DOI: 10.1021/acs.jmedchem.9b01608
  3. View record in Web of Science®
  4. WOS: 000509438800013

Library Notes

  1. Fiscal Year: FY2019-2020
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